The epidermal growth factor receptor family members, EGFR and HER2, are implicated in breast cancer radioresistance, and inhibitors of these receptors demonstrate effective radiosensitization in preclinical models and early stage clinical trials. Since both EGFR and HER2 are involved in breast cancer pathogenesis, inhibitors that target both of these receptors may have wider applicability than those that target just one receptor. Indeed, preclinical data indicates that the dual EGFR/HER2 inhibitor, GW572016, has antiproliferative and radiosensitizing effects on both EGFR and HER2 over-expressing breast cancer cell lines. The broad objective of this study is to evaluate the toxicity and biologic activity of GW572016 in combination with radiotherapy for locoregionally recurrent or refractory breast cancer. We hypothesize that GW572016 will be well-tolerated when given concurrently with radiotherapy, and will radiosensitize locally recurrent breast cancer. Further we hypothesize that, despite inhibition of receptor phosphorylation, critical downstream signals will be inhibited in only a subset of tumors, and that inhibition of downstream signaling will correlate with radiosensitization. This is a phase I study of escalating doses of GW57201-G in combination with standard radiotherapy. Serial tumor biopsies will be obtained to determine inhibition of Ras-MAPK and PI3K-AKT as well as receptor phosphorylation. The primary objectives will be to evaluate toxicity of the combination and determine the effect of GW572016 on receptor and downstream signaling in the setting of radiation therapy; secondary endpoints will be to evaluate response and gain preliminary indication of correlation between response and inhibition of downstream signaling. Relevance: Despite modern adjuvant therapy, 5-20% of patients with early stage breast cancer will develop locoregional recurrence, and the majority of those will not be effectively treated with conventional therapy, with 5 year survival rates only 35-50%. Furthermore uncontrolled locoregional recurrence can be highly morbid causing pain, bleeding, and infection. This proposal pilots a novel combination therapy to treat this common and challenging clinical problem. [unreadable] [unreadable] [unreadable]